Research Spotlight

Solomon, S. D., A. R. Rizkala, J. Gong, W. Wang, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, M. M. Redfield, J. L. Rouleau, D. J. Van Veldhuisen, F. Zannad, M. R. Zile, A. S. Desai, V. C. Shi, M. P. Lefkowitz and J. J. V. McMurray (2017). “Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: Rationale and design of the paragon-hf trial.” JACC Heart Fail 5(7): 471-482.

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OBJECTIVES: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). BACKGROUND: HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. METHODS: The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction >/=45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. CONCLUSIONS: PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF].

Agopian, V. G., M. P. Harlander-Locke, R. M. Ruiz, G. B. Klintmalm, S. Senguttuvan, S. S. Florman, B. Haydel, M. Hoteit, M. H. Levine, D. D. Lee, C. B. Taner, E. C. Verna, K. J. Halazun, R. Abdelmessih, A. D. Tevar, A. Humar, F. Aucejo, W. C. Chapman, N. Vachharajani, M. H. Nguyen, M. L. Melcher, T. L. Nydam, C. Mobley, R. M. Ghobrial, B. Amundsen, J. F. Markmann, A. N. Langnas, C. A. Carney, J. Berumen, A. W. Hemming, D. L. Sudan, J. C. Hong, J. Kim, M. A. Zimmerman, A. Rana, M. L. Kueht, C. M. Jones, T. M. Fishbein and R. W. Busuttil (2017). “Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within milan criteria undergoing liver transplantation: Analysis of 3601 patients from the us multicenter hcc transplant consortium.” Ann Surg: 2017 Jun [Epub ahead of print].

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OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetorotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Bardia, A., I. A. Mayer, J. R. Diamond, R. L. Moroose, S. J. Isakoff, A. N. Starodub, N. C. Shah, J. O’Shaughnessy, K. Kalinsky, M. Guarino, V. Abramson, D. Juric, S. M. Tolaney, J. Berlin, W. A. Messersmith, A. J. Ocean, W. A. Wegener, P. Maliakal, R. M. Sharkey, S. V. Govindan, D. M. Goldenberg and L. T. Vahdat (2017). “Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (immu-132) in heavily pretreated patients with metastatic triple-negative breast cancer.” J Clin Oncol 35(19): 2141-2148.

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Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease >/= 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade >/= 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Basra, S. and M. Szerlip (2017). “Transcatheter aortic valve replacement and mitraclip to reverse heart failure.” Interv Cardiol Clin 6(3): 373-386.

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Valvular heart diseases such as aortic stenosis and mitral regurgitation are often associated with heart failure, which in turn increases patients’ Surgical Thoracic Society (STS) score. A high STS score means the patient is high risk for surgical aortic valve replacement and mitral valve repair/replacement. Transcatheter aortic valve replacement and percutaneous mitral valve repair offer a minimally invasive alternative for the treatment of valvular heart disease in patients with severe heart failure. We aim to review the current evidence on the safety, efficacy, and outcomes of these devices in patients with severe heart failure.

Carroll, J. D., S. Vemulapalli, D. Dai, R. Matsouaka, E. Blackstone, F. Edwards, F. A. Masoudi, M. Mack, E. D. Peterson, D. Holmes, J. S. Rumsfeld, E. M. Tuzcu and F. Grover (2017). “Procedural experience for transcatheter aortic valve replacement and relation to outcomes: The sts/acc tvt registry.” J Am Coll Cardiol 70(1): 29-41.

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BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been introduced into U.S. clinical practice with efforts to optimize outcomes and minimize the learning curve. OBJECTIVES: The goal of this study was to assess the degree to which increasing experience during the introduction of this procedure, separated from other outcome determinants including patient and procedural characteristics, is associated with outcomes. METHODS: The authors evaluated the association of hospital TAVR volume and patient outcomes for TAVR by using data from 42,988 commercial procedures conducted at 395 hospitals submitting to the Transcatheter Valve Therapy Registry from 2011 through 2015. Outcomes assessed included adjusted and unadjusted in-hospital major adverse events. RESULTS: Increasing site volume was associated with lower in-hospital risk-adjusted outcomes, including mortality (p < 0.02), vascular complications (p < 0.003), and bleeding (p < 0.001) but was not associated with stroke (p = 0.14). From the first case to the 400th case in the volume-outcome model, risk-adjusted adverse outcomes declined, including mortality (3.57% to 2.15%), bleeding (9.56% to 5.08%), vascular complications (6.11% to 4.20%), and stroke (2.03% to 1.66%). Vascular and bleeding volume-outcome associations were nonlinear with a higher risk of adverse outcomes in the first 100 cases. An association of procedure volume with risk-adjusted outcomes was also seen in the subgroup having transfemoral access. CONCLUSIONS: The initial adoption of TAVR into practice in the United States showed that increasing experience was associated with better outcomes. This association, whether deemed a prolonged learning curve or a manifestation of a volume-outcome relationship, suggested that concentrating experience in higher volume heart valve centers might be a means of improving outcomes.